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Vol. 18, Issue 1, 34-46, January 2007
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*Department of Physiology and Pathophysiology, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium; Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, Gakuin, Sanda 669-13, Japan; Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3; and Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
Submitted March 7, 2006;
Revised September 29, 2006;
Accepted October 19, 2006
Monitoring Editor: Asma Nusrat
Gap junction (GJ) channels are formed by two hemichannels (connexons), each contributed by the cells taking part in this direct cell–cell communication conduit. Hemichannels that do not interact with their counterparts on neighboring cells feature as a release pathway for small paracrine messengers such as nucleotides, glutamate, and prostaglandins. Connexins are phosphorylated by various kinases, and we compared the effect of various kinase-activating stimuli on GJ channels and hemichannels. Using peptides identical to a short connexin (Cx) amino acid sequence to specifically block hemichannels, we found that protein kinase C, Src, and lysophosphatidic acid (LPA) inhibited GJs and hemichannel-mediated ATP release in Cx43-expressing C6 glioma cells (C6-Cx43). Lipopolysaccharide (LPS) and basic fibroblast growth factor (bFGF) inhibited GJs, but they stimulated ATP release via hemichannels in C6-Cx43. LPS and bFGF inhibited hemichannel-mediated ATP release in HeLa-Cx43 cells, but they stimulated it in HeLa-Cx43 with a truncated carboxy-terminal (CT) domain or in HeLa-Cx26, which has a very short CT. Hemichannel potentiation by LPS was inhibited by blockers of the arachidonic acid metabolism, and arachidonic acid had a potentiating effect like LPS and bFGF. We conclude that GJ channels and hemichannels display similar or oppositely directed responses to modulatory influences, depending on the balance between kinase activity and the activity of the arachidonic acid pathway. Distinctive hemichannel responses to pathological stimulation with LPS or bFGF may serve to optimize the cell response, directed at strictly controlling cellular ATP release, switching from direct GJ communication to indirect paracrine signaling, or maximizing cell-protective strategies.
Address correspondence to: Luc Leybaert (luc.leybaert{at}ugent.be)
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